Oxidative stress is defined as an imbalance between the physiological systems of antioxidant protection and increased production of oxygen or nitrogen radicals by the cells of the immune system. The result can be damage to the molecular structure of proteins, sugars and lipids together with damage to the cell functions, which also prejudices the functions of the body's vital organs. Oxidative stress has been observed to be particularly evident in patients suffering from kidney failure and undergoing haemodialysis. This phenomenon is attributed to bioincompatibility between the patient's circulating blood cells and the dialysis membranes, together with other factors such as a chronic uraemic state. This bioincompatibility leads to excessive production of Reactive Oxygen Species (ROS) by the immune system, and at the same time a reduction in the antioxidant capacity of the body due to losses of antioxidant molecules such as glutathione (GSH), vitamin A, vitamin C and vitamin E through the filters of the dialysis membranes.
One of the consequences of this abnormal immune response is a condition of oxidative stress, which leads to greater susceptibility to infection due to the defective immune response, amyloidosis and accelerated atherosclerosis due to continual activation of the immunocompetent cells. This triggers an inflammatory response, with consequent continual release of cytokines and lysosomal proteolytic enzymes, and stimulation of free radical production; in practice the oxidative stress becomes a self-replicating process, and generates a condition of chronic inflammation.
The main consequence of oxidative stress is cardiovascular complications, which are the main cause of death in patients suffering from chronic kidney failure. At local level these complications are manifested by alterations of the endothelium, accumulation of lipids, formation of clots and occlusion of the lumen.
At systemic level, chronic oxidative stress stimulates acute-phase protein synthesis by the liver at the expense of synthesis of other proteins, such as albumin and transferrin: the result is malnutrition, which is exacerbated by catabolic breakdown of muscle proteins and reduced appetite.
The chronic renal failure (CRF) is a progressive disease of kidney; when the kidney has lost all its ability of clear the blood, the patients cannot survive and have to be submitted to the dialysis procedure. Such a last condition is defined End-Stage Renal-Disease (ESRD).
Examples of the treatment of oxidative stress by administering products with antioxidant activity are reported below. The product most often used for the prevention and treatment of oxidative stress at present is N-acetylcysteine (see, for example, Kidney Int., Vol 64 (2003), pp. 82-91; Current Med. Chem., 2003, 10, pp. 1241-53). In particular, WO 01/02004 describes the use of N-acetylcysteine by intravenous injection before and/or during haemodialysis treatment.
According to Nakanishi et al., Kidney Int. 2003 March; 63(3): 1137-40, the plasma concentration of cysteine and homocysteine increases in patients with chronic kidney failure who undergo dialysis. It consequently does not seem logical to further increase the cysteine concentration in these patients.
Santangelo F., Current Med. Chem., 2003, 10, 2599-2610, has recently reviewed the therapeutic uses of cysteine pro-drugs such as N-acetylcysteine and its esters, thiazolidines, γ-glutamylcysteine and glutathione esters, particularly discussing the importance of intracellular GSH concentration. The oral administration of cysteine or cystine rather than derivatives thereof has been however neither disclosed nor suggested by this review.